Paraneoplastic Cerebellar Degeneration Preceding the Diagnosis of Hodgkin’S Lymphoma

CA s E r E p o r T paraneoplastic cerebellar degeneration preceding the diagnosis of hodgkin’s lymphoma P.F. Ypma1*, P.W. Wijermans1, H. Koppen2, P.A.E. Sillevis Smitt3 Departments of 1Haematology and Neurology, HagaZiekenhuis, location Leyenburg, Leyweg 75, 545 CH The Hague, the Netherlands, 3Department of Neurology, Erasmus Medical Centre, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands, *corresponding author: tel.: +31 (0)70-359 5 56, fax: +31 (0)70-359 22 09, e-mail: [email protected] A B s T r act i N T r o d u ct i o N paraneoplastic cerebellar degeneration (pCd) can present Paraneoplastic cerebellar degeneration (PCD) typically as a severe and (sub)acute cerebellar syndrome. pCd presents with (sub)acute, severe cerebellar ataxia.1 PCD can accompany different kinds of neoplasms including is most commonly associated with small cell lung cancer small cell lung cancer, adenocarcinoma of the breast and (SCLC), adenocarcinoma of the breast and ovary, followed ovary, and hodgkin’s lymphoma. A 34-year-old patient is by Hodgkin’s lymphoma.2 Sometimes the diagnosis described with acute dysarthria, gait ataxia and diplopia. of a malignant disease is made before the syndrome despite extensive laboratory and radiological evaluations in occurs. Usually, however, PCD precedes the underlying this patient with rapidly deteriorating cerebellar syndrome, neoplastic disease, posing a diagnostic challenge. The the diagnosis of a paraneoplastic syndrome was only detection of antineuronal autoantibodies directed against made after several months, when an anti-Tr antibody was onconeural antigens helps diagnose the neurological detected in his serum. The search for hodgkin’s disease syndrome as paraneoplastic and directs the search for an as concomitant disorder was then started and resulted underlying tumour.3-5 The autoantibodies associated with in stage IIB disease. The patient was successively treated PCD include anti-Hu (SCLC), anti-Yo (breast and ovarian with six courses of etoposide, bleomycin, vinblastine and cancer) and anti-Tr (Hodgkin’s disease). In 1976, Trotter dexamethasone and radiotherapy, which resulted in a et al. described an autoantibody in the serum of a patient complete remission of the hodgkin’s disease. After starting with Hodgkin’s lymphoma directed against cerebellar therapy the cerebellar degeneration stabilised. Purkinje cells and held the antibody responsible for The pathogenesis of neuronal damage in central nervous the paraneoplastic symptoms.6 Other reports followed, system paraneoplastic disorders such as the one we describe but it was not until 1997 that Graus et al. found an is not completely understood. Antitumour therapy is anti-Purkinje cell antibody in five Hodgkin’s patients assumed to be the important cornerstone in stabilising with PCD showing a characteristic immunoreactivity the neurological condition. improvement of the cerebellar in the molecular layer of the cerebellum ( figure 1). The syndrome in anti-Tr autoantibody paraneoplastic disease is antibody was named anti-Tr after the first two letters of a rare achievement. Early recognition of the concomitant Dr Trotter’s name.7-9 Recently, Bernal et al. analysed a disorders (anti-Tr autoantibody disease and hodgkin’s series of 28 patients with PCD and anti-Tr antibodies. lymphoma) is of crucial importance. Of the 28 patients with anti-Tr immunoreactivity, 25 patients suffered from Hodgkin’s disease while three had no demonstrable tumour.1 Here we describe a patient K E y w o r d s presenting with an acute cerebellar syndrome leading to the diagnosis of Hodgkin’s lymphoma several months Anti-Tr, cerebellar degeneration, Hodgkin’s lymphoma, later. paraneoplastic © 2006 Van Zuiden Communications B.V. All rights reserved. July-August 2006, Vol. 64, No. 7 43 scan (before and after administration of gadolineum figure 1. Paraffin sections of rat cerebellum incubated contrast medium) were normal. Cerebrospinal fluid with biotynilated immunoglobulin G from an anti-Tr examination revealed pleiocytosis with lymphocyte counts positive serum, counterstained with haematoxylin of 462/3, glucose 3.47 mmol/l and total protein of 0.73 g/l. Furthermore a monoclonal IgG was present which was not found in the serum (IgG index 0.74). Microbiological examination of the cerebrospinal fluid (CSF) remained negative. Immunophenotyping of blood and CSF showed no monoclonal cell population. In the blood 16% of all mononuclear cells were B-cells and of all T cells, 43% showed CD4 expression, 26% CD8 expression. There was no increase in NK-cells. In the CSF 24% of all cells were B-lymphocytes and T-cell distribution CD4/CD8 cells equalled 3:1. CT scanning of the body did not show any malignancies, including lymphoma. A descriptive diagnosis of ‘lymphocytic meningitis’ was made but the cause of the severe cerebellar syndrome remained unclear. During the admission, the nystagmus disappeared spontaneously and the patient was discharged to a rehabilitation clinic. Some weeks later, the results of serum paraneoplastic antibody test, showed the presence of anti-Tr antibodies (titre 1:800), almost pathognomonic The typical anti-Tr pattern with punctate reactivity of the molecular for Hodgkin’s lymphoma. Physical examination showed a layer and staining of the cytoplasm and proximal dendrites of pathological lymph node in the right axilla. However, in purkinje cells is shown. the operating room, one week later, the lymph node had disappeared. Ultrasound examination also ruled out any axillary lymph node enlargement. FDG-PET scanning, C A s E r E p o r T again ten days later, showed increased FGD uptake in the right axilla and the neck (figure 3). Meanwhile, the patient A 34-year-old male was admitted to the neurology ward was treated with plasmapheresis in an attempt to alleviate because of acute dysarthria, gait ataxia and diplopia. the cerebellar syndrome by decreasing the autoantibody He complained of headache accompanied by nausea titre. During the plasmapheresis his clinical condition and vertigo. There was no fever or any other systemic stabilised. An axillary lymph node became palpable again symptom at the time of presentation. Several months and biopsy demonstrated a Hodgkin’s lymphoma, nodular before admission, his family doctor had started him on sclerosing type. Ann Arbor staging revealed stage IIB, paroxetine (30 mg daily) for depression. He smoked 20 weight loss occurred within several weeks as well as cigarettes daily and had four to six alcoholic drinks during itching. At the start of his first chemotherapy cycle, i.e. the weekend. Physical examination showed a slightly etoposide, bleomycin, vinblastine and prednisone (EBVP), apathetic man without signs of meningeal irritation. He the antibody titre had risen to 1:3200. After two cycles had normal blood pressure (135/85 mmHg), pulse (90 of chemotherapy the titre had decreased to 1:800. The beats/min) and temperature of (37.5°C). His speech was lymph nodes also decreased rapidly and were not palpable dysarthric and there was a third-grade nystagmus to the after two cycles. After the sixth cycle of EBVP the anti-Tr left. No cranial nerve dysfunction or visual disturbances antibody was no longer detectable (figure 4). CT scan of the were noticed. Sensory examination and strength were body showed complete remission after chemotherapy and normal. The finger-nose and heel-shin test were severely involved field radiotherapy. The cerebellar syndrome had ataxic and the patient was incapable of walking without stabilised, but the patient still was incapable of walking help, due to an unsteady and wide-based ataxic gate. without help and spoke in a dysarthric manner. No Laboratory tests showed no signs of infection, and the neurotoxic effects of vinblastine were observed. This was erythrocyte sedimentation rate was 13 mm (in the first carefully examined, as it is a reported side effect of this hour). Renal function, liver enzymes, glucose, alcohol cytostatic drug. CT scan of the brain six months after the level, serological tests (Lues, HIV, Lyme’s disease, herpes first symptoms showed marked degeneration of gyri and viruses, ANF), vitamin E level, angiotensin-converting widening of sulci of the cerebellum, indicating that supra- enzyme and tumour marker tests did not reveal the cause and infratentorial (cerebellar) tissue loss had occurred of the symptoms. Cerebral CT scan (figure 2A) and MR (figure 2B). Ypma, et al. PCD preceding the diagnosis of Hodgkin’s lymphoma. July-August 2006, Vol. 64, No. 7 44 figure 2. CT scan of the cerebrum of the patient described at diagnosis (A) and showing widening of the supratentorial ventricular system and the sulci of the cerebellum as a sign of tissue loss six months later (B; arrows) A B figure 3. 18Fluorodeoxyglucose positron emission figure 4. Concentration of anti-Tr antibody measured tomography of the patient described in serum of the patient described 3500 3000 500 000 1500 1000 500 0 Jan Feb Mar Apr May JunJul Aug 2003 Titre 1 After the sixth cycle of chemotherapy the anti-Tr antibody titre had disappeared. still not understood, the presence of high titre antibodies directed against antigens in cerebellar Purkinje cells, the FDG uptake is striking in the neck and right axilla as a sign of intrathecal synthesis of these antibodies and the presence localisation of the malignant disease. uptake of FDG in the urinary of inflammatory infiltrates in the cerebellum strongly point bladder is considered physiological. to an autoimmune process. Anti-Tr antibody was named after John L. Trotter, who described a 21-year-old female with stage I Hodgkin’s disease and cerebellar ataxia.6,7 d i s C u s s i o N Serum of the patient showed strong immunofluorescent staining of cerebellar Purkinje cells on sections of normal With small cell lung, breast and ovarian cancer, Hodgkin’s human cerebellar tissue.6 Anti-Tr is identified by its lymphoma belongs to the malignancies most often immunohistochemical staining pattern in fixed frozen associated with PCD.2,3 The possible association between cerebellar sections.

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